Acute respiratory distress syndrome (ARDS) is most commonly due to severe pneumonia or sepsis. Decades of intense study have focused on the initial inflammatory phase of ARDS, and yet mortality rates for ARDS are still very high because newer pharmocotherapies have not emerged. In this Program Project Grant competing renewal application, we have assembled a team of world-class leaders with complementary expertise to investigate a new pathophysiologic model that challenges the existing concept that ARDS is solely a hyper-inflammatory disorder. In this model, we will investigate a novel concept that in ARDS, immunosuppression is a signature manifestation in a subset of patients secondary to unique, combinatorial pathways that modulate epithelial and myeloid cell viability and innate immune function. We hypothesize that immune suppression occurs via chromatin remodeling and ubiquitin- degradative pathways (Project 1), through a set of distinct cell death pathways including a new form of oxidation driven, non-apoptotic cell death termed ferroptosis (Project 2), through a phenotypic shift from loss of crucial host-protective lymphocytes (CD8+, MAIT cells) to immunosuppressive myeloid cells (Project 3), and oxidation-mediated impairment of macrophage bacterial killing and phagocytosis (Project 4). To evaluate this hypothesis, investigators will employ state-of-art molecular, cell, human-based systems, and lipidomic tools. These approaches will be translated to complementary 2- hit models of lung injury and immunosuppression and analysis in ARDS human subjects. The Program will be supported by two highly interactive Cores with expertise in human biorepository services and bioimaging. Execution of these studies will provide a paradigm-changing conceptual model for ARDS pathogenesis that serves as a basis for therapeutic intervention and providing a new and sustained field of scientific inquiry in lung biology.